KO-2806 Monotherapy and Combination Therapies in Advanced Solid Tumors

Official title

Phase 1, First-in-Human, Multicenter, Open-Label Study to Evaluate the Safety, Tolerability, Pharmacokinetics, Pharmacodynamics, and Preliminary Antitumor Activity of KO-2806 When Administered as Monotherapy and in Combination Therapy in Adult Patients With Advanced Solid Tumors

Overview

This first-in-human (FIH) dose-escalation and dose-validation/expansion study will assess KO-2806, a farnesyltransferase inhibitor (FTI), as a monotherapy and in combination, in adult patients with advanced solid tumors.

Interventions

• Drug Darlifarnib
  Oral administration
• Drug Cabozantinib
  Oral administration
• Drug Adagrasib
  Oral administration

Primary outcome measures

• Rate of dose-limiting toxicities (DLTs) [Time frame: DLTs will be evaluated during the first 28 days of KO-2806 treatment (dose escalation)]
• Descriptive statistics of adverse events (AEs) [Time frame: First dose of KO-2806 up to and including 28 days after last dose of KO-2806 (dose escalation)]
• Incidence of dose interruptions, reductions, and discontinuations due to AE [Time frame: First dose of KO-2806 up to last dose of KO-2806 or up to 24 months of treatment (dose escalation)]
• Objective Response Rate (ORR) [Time frame: Up to an estimated period of 24 months (dose expansion)]

Secondary outcome measures (12)

• Incidence of dose interruptions, reductions, and discontinuations due to AE [Time frame: First dose of KO-2806 up to last dose of KO-2806 or up to 24 months of treatment (dose expansion)]
• Descriptive statistics of AEs [Time frame: First dose of KO-2806 up to and including 28 days after last dose of KO-2806 (dose expansion)]
• Objective Response Rate (ORR) [Time frame: Up to an estimated period of 24 months (dose escalation)]
• Disease control rate (DCR) [Time frame: Up to an estimated period of 24 months (dose escalation and expansion)]
• Duration of response (DoR) [Time frame: Up to an estimated period of 24 months (dose escalation and expansion)]
• Time to response (TTR) [Time frame: Up to an estimated period of 24 months (dose escalation and expansion)]
• Progression-Free Survival (PFS) [Time frame: Up to an estimated period of 24 months (dose escalation and expansion)]
• Overall Survival (OS) [Time frame: First dose of KO-2806 until death, or up to an estimated period of 37 months (dose escalation and expansion)]
• AUClast [Time frame: Cycle 1. Each cycle is 28 days. (Dose escalation and dose expansion)]
• AUC0-inf [Time frame: Cycle 1. Each cycle is 28 days. (Dose escalation and dose expansion)]
• Cmax [Time frame: Cycle 1. Each cycle is 28 days. (Dose escalation and dose expansion)]
• Cmin [Time frame: Cycle 1. Each cycle is 28 days. (Dose escalation and dose expansion)]

Eligibility criteria

Inclusion criteria

• At least 18 years of age.
• Histologically or cytologically confirmed advanced solid tumors

• Arm #1 (KO-2806 monotherapy): Patients who have progressed on, or are refractory to, standard of care (SOC) treatments with advanced solid tumors, specifically: HRAS-mutant and/or amplified tumors (any solid tumor type); HRAS overexpression (only for HNSCC tumors); KRAS and/or NRAS, and/or HRAS-mutant and/or amplified NSCLC or CRC; KRAS-mutant and/or amplified PDAC
• Arm #2 (Combination): Patients who have received at least 1 prior systemic therapy with IO-based treatment for locally advanced or metastatic RCC with predominantly clear cell subtype; non-clear cell RCC patients who are either treatment-naïve or have received any prior systemic treatment for locally advanced and metastatic RCC.
• Arm #3 (Combination): Patients who have received at least 1 prior systemic therapy including available approved SOC treatments for KRAS G12C-mutant locally advanced or metastatic NSCLC, CRC, or PDAC.
• Arm #4 (Combination): Patients must be cabozantinib-naïve and have received at least 1 prior systemic therapy with IO-based treatment for locally advanced or metastatic ccRCC, but no more than 3 prior systemic anticancer therapies.
• Arm #5 (Cabozantinib monotherapy): Patients must be cabozantinib-naïve and have received at least 1 prior systemic therapy with IO-based treatment for locally advanced or metastatic ccRCC, but no more than 3 prior systemic anticancer therapies.
• Arm #6 (Cabozantinib rollover to combination): Patients must be cabozantinib-naïve and have received at least 1 prior systemic therapy with IO-based treatment for locally advanced or metastatic ccRCC, but no more than 3 prior systemic anticancer therapies.
• Arm #7 (Combination): Patients who have received at least 1 prior systemic therapy including available approved SOC treatments for KRAS G12C-mutant locally advanced or metastatic NSCLC
• Measurable disease by Response Evaluation Criteria in Solid Tumors (RECIST) v1.1.
• Karnofsky Performance Status of 70 or higher with no clinically significant deterioration over the previous 2 weeks.
• Acceptable liver, renal, endocrine, and hematologic function.
• Other protocol-defined inclusion criteria may apply.

Exclusion criteria

• Any use of anticancer therapy within 14 days or 5 half-lives (whichever is shorter) of Cycle 1 Day 1.
• Prior treatment with an FTI or HRAS inhibitor.
• Major surgery, other than local procedures, within 28 days prior to Cycle 1 Day 1, without complete recovery.
• Spinal cord compression, leptomeningeal disease, or clinically active CNS metastases.
• Toxicity (excluding alopecia) from prior therapy that has not been completely resolved to baseline at the time of consent.
• Active or prior documented autoimmune or inflammatory disorders within the past 5 years prior to Cycle 1 Day 1 (with exceptions).
• Active, uncontrolled bacterial, viral, or fungal infections requiring systemic therapy.
• Inability to swallow, impairment of gastrointestinal (GI) function or GI disease that may significantly alter the absorption of the trial drugs.
• Inadequate cardiac and/or vascular function, including receipt of treatment for unstable angina, myocardial infarction, and/or cerebrovascular attack within the prior 6 months, mean QTcF ≥470 ms, or Class II or greater congestive heart failure.
• Other invasive malignancy within 2 years.
• Other protocol-defined exclusion criteria may apply.

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: No

Study design

Allocation

Non-randomized

Model

Sequential

Masking

Open label

Primary purpose

Treatment

Study locations

United States · 22 centers

• Mayo Clinic Comprehensive Cancer Center — Phoenix
• University of Arizona — Tucson
• University of Southern California — Los Angeles
• Cedars-Sinai Medical Center — Los Angeles
• UCLA Department of Medicine — Los Angeles
• Sarah Cannon Research Institute at HealthONE — Denver
• AdventHealth Celebration — Celebration
• Mayo Clinic Comprehensive Cancer Center — Jacksonville
• … and 14 more centers

Italy · 5 centers

• Azienda Ospedaliera Universitaria Policlinico Sant'Orsola Malpighi IRCCS — Bologna
• Fondazione Piemonte per l'Oncologia - IRCCs Candiolo — Candiolo
• Istituto Nazionale Tumori IRCCS — Naples
• Humanitas University — Rozzano
• AOU Verona - Centro Ricerche Cliniche di Verona — Verona

France · 4 centers

• Centre Leon Berard — Lyon
• Oncologie médicale - Pitié-Salpêtrière — Paris
• Hopital Européen Georges Pompidou — Paris
• Institut Universitaire du Cancer Toulouse - Oncopole — Toulouse

Spain · 4 centers

• Hospital Universitari Vall d'Hebron — Barcelona
• Hospital de la Santa Creu i de Sant Pau — Barcelona
• Hospital HM Sanchinarro START Madrid-CIOCC — Madrid
• Hospital Universitario Virgen del Rocío — Seville

Germany · 3 centers

• Charité - Universitätsmedizin Berlin — Berlin
• Universitätsklinikum Ulm — Ulm
• Universitätsklinikum Würzburg — Würzburg

Identifiers

NCT: NCT06026410 · KO-2806-001

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗